Friday, June 28, 2013

A number of scientists have been vocal proponents of study pre-registration, in which detailed methodological and statistical plans for an experiment are registered in advance of data collection. The admirable goal is to eliminate questionable research practices such as failing to report all of a study's dependent measures, deciding whether to collect more data after looking to see whether the results are significant, and selectively reporting studies that 'worked.' Along these lines, the journal Cortex has recently launched a new type of article called Registered Reports, largely through the efforts of Dr Chris Chambers:

Unlike conventional publishing models, Registered Reports split the review process into two stages. Initially, experimental methods and proposed analyses are pre-registered and reviewed before data are collected. Then, if peer reviews are favourable, we offer authors “in-principle acceptance” of their paper. This guarantees publication of their future results providing that they adhere precisely to their registered protocol. Once their experiment is complete, authors then resubmit their full manuscript for final consideration.

Many of these same researchers are also strong advocates for publication reform, some even calling for journals to be eliminated altogether in favor of post-publication, crowd-sourced review and reputation ranking. But supporters of both pre-registration and the Open Science Framework haven't yet utilized its capability to submit their new work (as opposed to the Reproducibility Project for replications).

Since calls for pre-registration of basic research studies have been ongoing for years, perhaps its proponents have been too conservative with taking matters into their own hands. One might even say there's a distinct lack of risk-taking among the strongest believers. What's to prevent them from pre-registering studies in public databases or on their own blogs (without formal peer review but perhaps soliciting comments)? Or publishing a Study Protocol in a BMC journal (like @SallyScientist did)?

Take the USA Today article above. It wasn't an egregious offender, yet it used an unfortunate mixed metaphor to make a point:

The brain is the temple of the mind, but are images of it in action a little over-worshipped?

The 'temple of the mind' terminology was from a Nature News story on the structure of the rat glutamate receptor GluA2. I found it bizarre that a reference to an article on protein crystallography, a method that produces an atomic-level picture of a single protein, was being used to prop up the 'seductive allure' of human brain images (a finding which hasn't replicated). In turn, someone decided that 'temple of the mind' was an appropriate way to describe the structure of the GluA2 receptor.2

...Tallis's beef is not just with crude methodologies. In detail so pitiless it threatens to be unreadable in parts, Aping Mankind argues that neuroscientific approaches to things like love, wisdom, and beauty are flawed because you can't reduce the mind to brain activity alone.

I believe that the brain is the ultimate arbiter of behavior (and that "the mind" is ultimately reducible to brain activity), but this doesn't preclude the view that interpersonal and social factors influence people's actions. Does anyone actually think that brains exist in isolation from any complex external influence (other than sensory stimulation)? It's a false dichotomy and a straw man argument foisted on neuroscientists by the neurotrashers. There are many different levels of analysis within the field, from molecules to synapses to systems to behavior.

Graduate neuroscience programs are interdisciplinary in nature, and subfields like Cultural Neuroscience and Neuroanthropology are on the leading edge of incorporating culture into brain function (and vice versa). But very few fields cover that broad a scope.

Scientists and scholars in various disciplines generally do specialized research based on narrow areas of expertise. Are historians negligent because they're not incorporating knowledge of the brain into their analyses of past events? Of course not. So why are neuroscientists remiss if they fail to include detailed sociological and developmental accounts of crime in their Human Brain Mapping journal articles? 3

It's not surprising that each discipline privileges one level of explanation over another. The danger lies in discarding all other explanatory models in favor of your own. This also holds for theorizing within a field.

The crudity of Adrian Raine's opening arguments in The Anatomy of Violence – his manifesto for neurocriminology – is curiously refreshing. It is a long time since evolutionary psychology was served so neat.

It is probably impossible to look at a map of
brain activity and predict or even understand the emotions, reactions,
hopes and desires of the mind.

The first basic problem is that regions of the brain handle a wide variety of different tasks. As Sally Satel and Scott O. Lilienfeld explained in their compelling and highly readable book, “Brainwashed: The Seductive Appeal of Mindless Neuroscience,” you put somebody in an fMRI machine and see that the amygdala or the insula lights up during certain activities. But the amygdala lights up during fear, happiness, novelty, anger or sexual arousal (at least in women). The insula plays a
role in processing trust, insight, empathy, aversion and disbelief. So what are you really looking at?

...the uses and abuses of neuroscience and brain imaging. Sally and Scott describe their book as an anchor in this discussion to expose "MINDLESS NEUROSCIENCE" and also as a critique of the assumption that the brain is the most important level of analysis for understanding human behavior.

Brooks began by talking about himself, presenting a revisionist history of his own pop neuro cheerleading, saying that in his own writings neuroscience didn't help that much, but experimental psychology helped him a lot.

"I wrote a book a few years ago about mindless neuroscience, and it did very well, so you can explain the seductive appeal of that book."

... "I started a book that I thought was going to popularize neuroscientific findings and how it'd apply to public policy and the sort of things that apply in this world, the world we deal with here in this building [the American Enterprise Institute]."

The Positive Side of the Cognitive Neuroscience Revolution

Brooks asked each of the speakers about the bright side of brain science "before we talk about the extremism." What follows below are my notes and paraphrases of the conversation.

Lilienfeld said the field was "brainless" when he came of age in the 80s and 90s -- genetics could not possibly cause behavior. Environmental factors were the primary causes of autism and schizophrenia. [NOTE: I found this a bit odd, since he attended graduate school at the University of Minnesota, site of the famous Minnesota twin studies. But I wasn't there, so what do I know.] Ultimately, injection of neuroscience was helpful, he said.

Satel mentioned the 70s biological revolution in psyschiatry. In her fields of addiction and PTSD, she felt things were too biological. She worked with Vietnam veterans with PTSD, noting both a biological component (failure of fear extinction, adrenergic system, hypothalamus, etc.) plus a profound existential dimension -- a challenge or threat that undermined integrity -- "the meaning they attributed to it was as important as the mechanism, and they both interacted" -- we should come back to somewhere in the middle. "Not to lose the mind in the age of brain science."

Democrat Brain, Republican Brain

A bit of conservative humor was injected into this portion of the conversation. Brooks mentioned the infamous This Is Your Brain on Politics opinion piece that masqueraded as actual science. "Very good pictures, aside from the fact that one is obviously a lot larger, more crenulated." [NOTE: perhaps he meant convoluted?]

"Was that a typically accurate story? If we scanned the brains here [AEI] and the Brookings brains would we see a big difference?"

Lilienfeld: "No." Ha ha [laughter].

Satel: "Yeah, ours would be bigger." Ha ha. She said that article ...was a bit of a fiasco -- one of the articles that called our attention to this. Almost read as a parody. Made a mockery of fMRI.

Free Will and Addiction

This might be considered the most controversial portion of the program, since it had policy implications. Brooks called the highbrow version of determinism "nothing but neurons" (Brian Appleyard - "nothing but-ism"), where neuroscience will replace psychology. [NOTE: There is well-articulated philosophical version of this view called eliminative materialism.] So we have no free will.

Satel (being more measured and erudite than Brooks) said there are a lot of steps in there... We're materialists, decapitation will prove it.

Which phenomena are best observed at level of the brain vs. at the level of the mind? Satel said that addiction illustrates the problem of 'neurocentrism' (neurons genes transmitters proteins) -- it's a good approach for curing Alzheimer's disease but not for dealing with addiction. Neural underpinnings underlie addiction, sure, but if you're a clinician or a policy maker is that the best way to interact with patients or develop policies? NO, she said. Regarding those with addictions: "in some ways their situation is fundamentally voluntary - let me define that - it's not easy to throw away that meth pipe but do these brain changes make them so helpless or out of control that they can't modify their behavior in response to reason or incentive or consequences?"

Brooks asked how do we define the boundary in this case?

Satel answered that "most people do overcome their addiction" - she referred to the clinician's illusion - they see the worst patients who have comorbidities - but "most people make a choice" - life is hard - essentially it's a self-medicating enterprise. In essence, she suggested that most people quit drugs/alcohol on their own, and that it's a matter of free will. Propensities for addiction and changes in the brain due to substance abuse be damned.

Lilienfeld said that the free will vs. determinism debate will not be resolvable any time soon. Interestingly, he holds the view that neuroscience does not inform free will debate, because it still doesn't say whether there's a ghost in machine even if determinist. [NOTE: uh....] There's no question that people make decisons in everyday life -- but rarely does addiction make it impossible, he said.

The Q & A with a bunch of old white guys in the audience (and three young white guys) was about half way through the video.

There we learn that Lilienfeld is a reductionist but not an eliminative materialist. An interesting point comes up when he addresses RDoC, one that somewhat questions his reductionist credentials. He's afraid of privileging biological indices as best way of measuring a psychological system. "If you want to find out if someone's an impulsive person, you ask them 'are you an impulsive person?' or you could give them laboratory tests and brain imaging. Will the latter tests give more information that just asking them and their families? We don't know that," he said.

Brooks blurts out, "That seems ridiculous to me! If you want to take an impulsive person you flick them on the ear and see what they do."

Or perhaps you give them a microphone and a column in the New York Times and see what they do...

Satel ends the conversation by mentioning their book's contribution to general neuroliteracy and "...how these levels of analysis can be bridged.1 ... ...it's a highly dynamic system that goes back and forth, and not to get seduced by these beautiful pictures which led to our preferred title, which was 50 Shades of Grey Matter." 2

-- Scott Lilienfeld
received his BA in Psychology from Cornell University in 1982 and his
PhD in Clinical Psychology from the University of Minnesota in 1990.

-- Sally Satel [PDF
of CV] received her BS from Cornell University in 1977, her MS from the
University of Chicago in 1980, and her MD from Brown University in
1984.

So that's the movie version of the book (which I have not read, other than excerpts). Neuroskeptic wrote an actual book review:

I wanted to dislike this book.

You see, I was suspicious of the fact that one of the authors is a resident scholar with the American Enterprise Institute (AEI),
an organization whose political values I oppose, and, insofar as it’s
an organization with political values, has little business going near
science.

Then, when I found that the book cites me (with fellow neurobloggers Mind Hacks and Neurocritic)
in the Acknowledgements and elsewhere, that actually made it worse. A
sense of intellectual possessiveness joined my ideological reasons for
not liking the thing.3

I was hoping that it would be dreadful so that I could unleash the
venom I had brewed up: “Ayn Rand, Please Get Off My Bandwagon”; “The
only good bits here are the bits they stole from me” – it would have
been glorious.

However, sadly, Brainwashed turned out to be good.

As usual, the book was better than the movie.

Footnotes

1 Those "levels of analysis in neuroscience" figures are as old as time, so there might not be much new ground covered there. Behavior is an explicit part of many of these. It's not a new concept to cognitive scientists, either.

3 I reacted the same way when I first read an excerpt of the book in Salon (Pop Neuroscience is Bunk!). I had blogged about at least 18 of the examples given in that excerpt alone, so I felt that someone else had written a book based largely on neuroblogs (mine and others).

Friday, June 14, 2013

Is a laboratory test or brain scanning method for diagnosing psychiatric disorders right around the corner? How about a test to choose the best method of treatment? Many labs around the world are working to solve these problems, but we don't yet have such diagnostic procedures (despite what some might claim). A new study by McGrath et al. (2013) might be a step in that direction, but the results are very preliminary and await further validation.

The choice of treatment modality in depression, as in other psychiatric disorders, is by trial and error. If one drug doesn't work, switch to another one. If your insurance covers it, a short course of evidence-based psychotherapy1 might be in order.

The whole concept of a DSM-based classification scheme for mental illnesses has come under fire, especially with the release of the new Diagnostic and Statistical Manual. In the real world, psychiatric disorders don't always show such clear boundaries; overlap and co-morbidity are common. The National Institute of Mental Health has endorsed a new approach, the Research Domain Criteria project, that incorporates dimensions of observable behavior along with neurobiological measures.

To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy.

Fewer than 40% of depressed patients remit with their first course of treatment, so this would be an important advance. A more scientific way of choosing among possible treatment options would benefit patients and society at large.

The study (registered at clinicaltrials.gov, NCT00367341) enrolled a total of 82 depressed people. The neuroimaging method might surprise some of you: FDG-PET to measure glucose metabolism -- not the popular and trendy resting state fMRI to examine functional connectivity or any sort of fMRI activation study. However, the authors cite an established literature using this technique in studies of antidepressant treatment response.

Patients diagnosed with moderate to severe depression (a score of 18 or more on the Hamilton Depression Rating Scale, HDRS) received a PET scan and were randomized to receive 12 weeks of either cognitive behavioral therapy (CBT, n=41) or escitalopram (Lexapro, n=39), an SSRI antidepressant. Sixty-three patients completed this phase and also had a PET scan. The endpoint considered a successful response to treatment was remission (HDRS score of 7 or less), while non-response was a change in HDRS of 30% or less. Partial responders were omitted, leaving the final groups as follows:

CBT remission, n=12

escitalopram remission, n=11

CBT nonresponse, n=9

escitalopram nonresponse, n=6

Right away we see that the number of patients in each group is very small, particularly for a study designed to identify biomarkers that will generalize to a larger population. Let me repeat that: a successful biomarker must generalize to an independent population. We haven't seen that here, so any conclusions drawn from this paper must be considered very preliminary.

How was the biomarker identified? The PET images were co-registered with the corresponding structural MRIs. A whole brain analysis identified regions showing a treatment × outcome interaction (at a significance level of p<.001 uncorrected). Six regions met this uncorrected standard: right anterior insula, right inferior temporal cortex, left amygdala,2 left premotor cortex, right motor cortex, and precuneus (medial superior parietal lobe). Most of these are pretty surprising, but even more surprising is that the rostral anterior cingulate (and subgenual cingulate, BA 25) were not involved:

Contrary to past published studies,63 the rostral anterior cingulate did not discriminate the outcome subgroups in either the main effect or interaction analyses. A post hoc examination of responder and nonresponder differences within each treatment arm did reveal a nonsignificant rostral cingulate activity difference, with metabolism in responders greater than nonresponders, but solely in the escitalopram group. While consistent with past reports, this finding did not meet the TSB [treatment-specific biomarker] criteria defined for the current study, ie, a region whose activity can differentiate both good and poor outcomes for both treatments.

- click on image for a larger view -

Effect sizes are shown in the table above. The brain regions were ranked in order of size of activation (which doesn't make sense for the amygdala), and the right anterior insula was chosen as the best potential biomarker because.... it had the largest cluster size? Or because it did marginally better than the other regions in terms of effect size (although this was not shown statistically). As a hub for interoceptive awareness, attention, and emotion, the anterior insula makes the most sense scientifically (Craig, 2009). Certainly, it would be odd if glucose metabolism in the right motor cortex could predict response to CBT or SSRI...

At any rate, right insula hypometabolism at baseline was associated with remission to CBT and poor response to SSRI, and vice versa for hypermetabolism. There was overlap between the groups as shown below, but increasing the chances of successful treatment (even with no guarantees) would be better than a completely trial-and-error approach.3

A Nature news story says that Brain scan predicts best therapy for depression, but that would be a premature conclusion at best. Although this study might be considered promising, the results must be validated in larger independent samples of patients who are assigned to treatments according to their baseline insula PET scans.

With the newly prominent nattering nabobs of neuroimaging negativity, it's important to remember that it's not all neuroprattle and bunk. Some of this research is trying to alleviate human suffering.

How do scientists measure the physiological aspects of sexual arousal in women? A 2009 paper by Woodard and Diamond reviewed 45 years of research using instruments that measure female sexual function. These devices include the vaginal photoplethysmograph (right), vaginal and labial thermistors, pressure/compliance balloons, clitoral electromyography, and the electrovaginogram. For a full list, see Table 1 at the bottom of this post.

The authors note that these physiological measures do not correlate very well with subjective ratings of sexual arousal. Furthermore, clinicians who treat women with sexual dysfunctions are of two minds. Some say the distinction between female desire and arousal may be artificial (see DSM-5 changes, p. 13), while others maintain that the merger of female sexual arousal disorder (FSAD) with Hypoactive Sexual Desire Disorder (HSDD) will be disastrous (Clayton et al., 2012).

The previous post about Lybrido and Lybridos, the drugs in clinical trials for HSDD, talked briefly about Emotional Brain, the Dutch drug company that is developing them. Putting aside the manyobjections to the HSDD diagnosis for now, and the fact that the trials pathologize sexual boredom within marriage, the company has conducted some interesting studies1 to assess sexual desire.

Foremost among these is the development of an at-home testing environment, or ambulatory lab, to conduct studies of sexual function (Bloemers et al., 2010).

The participants must be so much more comfortable watching hardcore porn and measuring their own vaginal pulse amplitude and clitoral blood volume in the privacy of their homes, without the prying eyes of hoards of scientists in white lab coats (although some people might be into that).

The results of this study support our hypothesis that in healthy controls, clitoral and subjective laboratory measures of sexual arousal show stronger increases to erotic stimuli in the home environment than in the environment of the institutional laboratory. This effect was apparent in response to hardcore stimuli, but not to erotic fantasy. ... To our knowledge, this is the first study that investigates ecological validity of sexual psychophysiological measures by comparing those assessed in the institutional laboratory to those assessed at home with an ambulatory laboratory.

Footnote

1Albeit flawed studies, from a cognitive perspective (especially their implementation of an 'Emotional Stroop' task). I am not particularly qualified to comment on other aspects of this research.

Monday, June 03, 2013

A feature article in last week's New York Times Magazine served as an extended ad for a new book by Daniel Bergner, What Do Women Want? Adventures in the Science of Female Desire. It's filled with post-fashionable pop neuroscience and simplistic neurotransmitter stereotypes that rival those of Naomi Wolf (including her infamous “dopamine is the ultimate feminist chemical in the female brain” quote). The focus of Bergner’s article is on pharmaceutical treatments for the controversial diagnosis of Hypoactive Sexual Desire Disorder (HSDD), particularly the subtly named Lybrido (along with its younger sister, Lybridos).

The heavy-handed branding of Lybrido and Lybridos (both 'working titles') was fascinating to me. While trying to identify the marketing firm behind it, I discovered the trademark was abandoned 6 years ago by Emotional Brain, the Dutch drug company developing them. Finding the active ingredients in Lybrido and Lybridos wasn’t readily apparent from the Emotional Brain site. Nor was it immediately evident from the NYT article, which even used obfuscatory language:

“Female Viagra” is the way drugs like Lybrido and Lybridos tend to be discussed. But this is a misconception.

Actually, this is not a misconception. Both drugs contain a major male sex hormone plus a second ingredient: Lybrido is testosterone + sildenafil (Viagra), while Lybridos is testosterone + buspirone (a serotonin 5-HT1A receptor partial agonist). The two formulations are in clinical trials for variants of HSDD identified by Emotional Brain researchers and described in a three part series published in the Journal of Sexual Medicine. These pilot studies used the related PDE5 inhibitor, vardenafil (Levitra). PDE5 inhibitors are widely used to treat erectile dysfunction, so claims that Lybrido doesn’t affect physical function in women are disingenuous:

Viagra meddles with the arteries; it causes physical shifts that allow the penis to rise. A female-desire drug would be something else. It would adjust the primal and executive regions of the brain. It would reach into the psyche.

Nevertheless, plenty of women have voluntarily enrolled in the Lybrido trials. Bergner interviewed some of them to determine the reasons for seeking out an experimental treatment:

Every woman raised a mix of possible reasons. There were the demands of graduate school, the demands of children, the demands of work, medical issues, men who weren’t always as kind or nearly as engaged as they could be. But at bottom there seemed to be one common cause: they had all grown tired of sex with their long-term partners.

Why medicalize boredom within marriage?

…Lori Brotto, a psychologist at the University of British Columbia who has worked clinically with scores of H.S.D.D. patients and who recently led the American Psychiatric Association’s attempt to better delineate the condition in The Diagnostic and Statistical Manual of Mental Disorders. (H.S.D.D. is being reconceived as sexual interest/arousal disorder, S.I.A.D.) “The impact of relationship duration is something that comes up constantly,” she told me about her therapy sessions. “Sometimes I wonder whether it” — H.S.D.D. — “isn’t so much about libido as it is about boredom.”

Basically, to participate in the trials, a woman has to be in a stable, long-term monogamous relationship. How many female patients have tried couples counseling before turning to drugs? Or did they all take their advice from the Daily Mail?

What efforts have the husbands expended to improve the sexual relationship, what work have they put in to make themselves more desirable to their wives? Are they taking a pill to make them less loutish?

[Lybrido developer Adriaan] Tuiten didn’t openly acknowledge monogamy as the core of the desire problem, but he knew he couldn’t use single subjects who might well find new lovers during the course of the trials. Their results might have to be tossed out because, with or without chemical aids, new lovers bring surges of lust.

Did the clinical trials for Viagra require men to be monogamous?

Dopamine Is Impulse; Serotonin Is Inhibition and Organization

How do the drugs work to restore female desire? Based on very little evidence, they purportedly restore the balance of dopamine and serotonin, despite taking a sledgehammer approach. Here's where Mr. Bergner devolves into dopamine/serotonin stereotypes that are just as bad as those from Naomi Wolf, but more boring. Divorced from the personal, unable to understand the phenomenology of female desire from the inside, Bergner is left with sterile rehashes of rat lust from Ms. Wolf's guru, Dr. James G. Pfaus. He even resorts to the old 'SSRIs simply cure depression by increasing serotonin' saw:

...And then there’s serotonin, dopamine’s foil. It allows the advanced regions of the brain, the domains that lie high and forward, to exert what is termed executive function. Serotonin is a molecule of self-control. It instills calm, stability, coherence (and, too, a sense of well-being, which is why S.S.R.I.'s, by bathing the brain in serotonin, can counter depression). Roughly speaking, dopamine is impulse; serotonin is inhibition and organization. And in sexuality, as in other emotional realms, the two have to work in balance. If dopamine is far too dominant, craving can splinter into attentional chaos. If serotonin overwhelms, the rational can displace the randy.

To help predict which women will most benefit from which drug, Tuiten has blood drawn from each subject and examines genetic markers related to brain chemistry. Tuiten also asks subjects questions about their comfort with sexual feelings and fantasies. Since our dopamine and serotonin networks are reinforced or attenuated by all we learn, all we think and do, he believes that the answers may provide clues about a given woman’s neurotransmitter systems, which he uses as part of his diagnostic method.

The three part series in the Journal of Sexual Medicine might be worth a future post to describe the methods Tuiten et al. use to guide treatment and decide who gets which drug.

Dr. Helen Fisher, advisor for chemistry.com, developed the concept of four neurotransmitter “archetypes” in her quest for a better, more scientific brand of matchmaking.

Each of these chemistry types is associated with a dominant neurotransmitter or hormone (serotonin, testosterone, dopamine, estrogen). But she knows this is a metaphor and not to be taken literally. "We're a combination of all four systems," Fisher says in a USA Today article.

Neuroplasticity: It's a Girl Thing

Let's conclude with the most puzzling brain-based explanation for HSDD: it's neuroplasticity! I couldn't comprehend the logic of this paragraph, no matter how hard I tried. It's one of those sex-and-relationship-type accounts that's seemingly neuro-related but really devoid of actual neuroscientific content:

This interplay of experience and neural pathways is widely known as neuroplasticity. The brain is ever altering. And it is neuroplasticity that may help explain why hypoactive sexual desire disorder is a mostly female condition, why it seems that women, more than men, lose interest in having sex with their long-term partners. If boys and men tend to take in messages that manhood is defined by sex and power, and those messages encourage them to think about sex often, then those neural networks associated with desire will be regularly activated and will become stronger over time. If women, generally speaking, learn other lessons, that sexual desire and expression are not necessarily positive, and if therefore they don’t think as much about sex, then those same neural networks will be less stimulated and comparatively weak. The more robust the neural pathways of eros, the more prone you are to feel lust at home, even as stimuli dissipate with familiarity and habit.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.